Diastolic coronary perfusion detection for timed delivery of therapeutic and/or diagnostic agents

ABSTRACT

During diastolic coronary perfusion, blood perfuses through the heart via the coronary arteries. Delivery of a therapeutic and/or diagnostic agent to the heart during diastolic coronary perfusion allows the therapeutic and/or diagnostic agent to efficiently perfuse through the heart. A medical device according to the invention detects closure of the aortic valve of a heart, and initiates delivery of a therapeutic and/or diagnostic agent upon detection of aortic valve closure. The medical device detects aortic valve closure by processing a signal. Exemplary signals used by the medical device to detect aortic valve closure include left or right ventricular accelerometer signals, left or right ventricular flow signals, left or right ventricular pressure signals, aortic pressure signals, pulse pressure signals, systemic arterial pressure signals, electrogram signals, and phonocardiogram signals.

RELATED APPLICATION

This application is a divisional of U.S. patent application Ser. No.10/636,857, filed Aug. 7, 2003 entitled “DIASTOLIC CORONARY PERFUSIONDETECTION FOR TIMED DELIVERY OF THERAPEUTIC AND/OR DIAGNOSTIC AGENTS”,herein incorporated by reference in its entirety.

TECHNICAL FIELD

The invention relates to medical devices, and more particularly, tomedical devices that deliver therapeutic and/or diagnostic agents to aheart.

BACKGROUND OF THE INVENTION

Various conditions that afflict the heart are treated through deliveryof one or more therapeutic and/or diagnostic agents. A variety oftechniques involving delivery of biological, genetic, and/orpharmacological therapeutic and/or diagnostic agents to the heart areknown for treating conditions such as myocardial infarction (MI), bloodclots within the coronary arteries, cardiac arrhythmias, coronary arterydisease (CAD), heart failure (HF), or the like. For example, myoblasts,myocytes or stem cells may be delivered to the heart as a therapeuticand/or diagnostic agent to treat an MI (i.e., the death of muscle cellswithin the heart). As another example, anticoagulants such as warfarinor heparin, or enzymes such as Tissue type plasminogen activator (t-PA),Streptokinase or Urokinase are delivered to the heart to deter ordissolve blood clots within the coronary arteries.

Therapeutic and/or diagnostic agents are delivered into, for example, achamber of the heart, blood vessels near the heart, such as the aorta,or the pericardial sac of the heart. Typically, therapeutic and/ordiagnostic agents are delivered to the heart in the form of a bolususing an infusion apparatus, such as a pump or syringe, coupled to acatheter, and/or a hollow needle. However, it is generally understoodthat a small percentage (<10%) of a therapeutic and/or diagnostic agentdelivered as a bolus actually “perfuses” (e.g., enters the coronaryvasculature) of the heart, with the remaining therapeutic and/ordiagnostic agent escaping to the systemic circulation.

Consequently, a bolus must include substantially more than atherapeutically effective amount of the therapeutic and/or diagnosticagent, increasing the cost of the treatment, among other disadvantages.Where an implantable drug pump is used to deliver a therapeutic and/ordiagnostic agent to the heart, the requirement of excess therapeuticand/or diagnostic agent impacts the size and/or the refilling scheduleof a reservoir of a drug pump. Further, the portion of the deliveredtherapeutic and/or diagnostic agent lost to the systemic circulation mayhave unintended and potentially undesirable effects on systemic andperipheral tissues of the patient to whose heart the therapeutic and/ordiagnostic agent is intended to be delivered.

SUMMARY OF THE INVENTION

In general, the invention is directed to techniques for delivering atherapeutic and/or diagnostic agent to a heart during diastolic coronaryperfusion. A medical device detects closure of an aortic valve of theheart, and initiates delivery of the therapeutic and/or diagnostic agentupon detection of the closure of the aortic valve. Because thetherapeutic and/or diagnostic agent is delivered timed to the incidenceof coronary perfusion, a controlled relative amount of the therapeuticand/or diagnostic agent is allowed to enter the coronary vasculature ofthe heart, versus being lost to the systemic circulation, such as whendelivered using conventional therapeutic and/or diagnostic agentdelivery techniques.

Diastolic coronary perfusion occurs upon and for a period of time afterthe closing of the aortic valve. The aortic valve closes when thepressure in the aorta exceeds the pressure in the left ventricle. Afterthe aortic valve closes the pressure in the aorta increases slightly inresponse to the closing of the valve. This small increase in pressureforces blood from the aorta into the coronary arteries through thecoronary sinus of the heart.

A medical device to deliver a therapeutic and/or diagnostic agent duringcoronary perfusion includes a sensor to monitor activity within theheart and a processor. The sensor generates a signal that reflects theevents of left cardiac or ventricular activity, and the processorprocesses the signal to detect closure of the aortic valve. Theprocessor controls a pump, which in exemplary embodiments forms a partof the medical device, to deliver the therapeutic and/or diagnosticagent to the heart via a catheter, or the like, at a duration orinterval, including simultaneously, timed to aortic valve closure. Inexemplary embodiments, the medical device and drug pump are implantedwithin the patient, and a distal end of the catheter is fluidly coupledto the aorta to deliver the therapeutic and/or diagnostic agent into theaorta and thus, the heart.

In one embodiment, the invention is directed to a method comprisingreceiving a signal that reflects activity of a heart, processing thesignal to detect closure of an aortic valve of the heart, and initiatingdelivery of a therapeutic and/or diagnostic agent to the heart upondetection of closure of the aortic valve.

In another embodiment, the invention is directed to a medical devicecomprising a pump to deliver a therapeutic and/or diagnostic agent to aheart via a catheter and a processor. The processor receives a signalthat reflects activity of the heart, processes the signal to detectclosure of an aortic valve of the heart, and controls the drug pump todeliver the therapeutic and/or diagnostic agent to the heart upondetection of closure of the aortic valve.

In another embodiment, the invention is directed to a system comprisingof a catheter, a pump to deliver a therapeutic and/or diagnostic agentto a heart via the catheter, a sensor to generate a signal that reflectsactivity of the heart, and a processor to receive the signal. Theprocessor processes the signal to detect closure of an aortic valve ofthe heart, and controls the pump to deliver the therapeutic and/ordiagnostic agent to the heart upon detection of closure of the aorticvalve.

In another embodiment, the invention is directed to a computer-readablemedium containing instructions. The instructions cause a programmableprocessor to receive a signal that reflects activity of a heart, processthe signal to detect closure of an aortic valve of the heart, andcontrol a pump to deliver a therapeutic and/or diagnostic agent to theheart upon detection of closure of the aortic valve.

In another embodiment, the invention is directed to a system comprisingmeans for detecting activity within a heart and generating a signal as afunction of the activity, means for delivering a therapeutic and/ordiagnostic agent to the heart, and means for processing the signal todetect closure of an aortic valve of the heart and controlling thedelivery means to deliver the therapeutic and/or diagnostic agent upondetection of closure of the aortic valve.

By example, and without limitation, a diagnostic agent may include abolus, droplet(s) or stream of a contrast media used in conjunction witha machine vision system such as a fluoroscope and the like, or a dye orother fluid that adheres to or is metabolized to a perceptible state inthe presence of one or more tissue, metabolic or fluid flowirregularities. In the event that a contrast media is dispensed adelivery catheter may be utilized that having manually-timed contrastmedia delivery or an external contrast media pump synchronized to thecardiac cycle via telemetry, wired connection, or the like.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages of the invention will be apparent from thedescription and drawings, and from the claims.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a conceptual diagram illustrating an exemplary medical devicethat delivers a therapeutic and/or diagnostic agent to a heart accordingto the invention.

FIG. 2 is a block diagram further illustrating the device of FIG. 1.

FIG. 3 is a timing diagram illustrating exemplary signals processed bythe device of FIG. 1 to detect closure of an aortic valve of the heart.

FIG. 4 is a flowchart illustrating an exemplary method employed by themedical device of FIG. 1 to deliver a therapeutic and/or diagnosticagent to the heart.

FIG. 5 is a conceptual diagram illustrating another exemplary medicaldevice that delivers a therapeutic and/or diagnostic agent to a heartaccording to the invention.

FIG. 6 is a conceptual diagram illustrating yet another exemplarymedical device that delivers a therapeutic and/or diagnostic agent to aheart according to the invention.

DETAILED DESCRIPTION OF THE DRAWINGS

FIG. 1 is a conceptual diagram illustrating an exemplary therapeuticand/or diagnostic agent delivery device 10 that delivers a therapeuticand/or diagnostic agent to a heart 12 according to the invention. Inexemplary embodiments, as shown in FIG. 1, device 10 is implanted withina patient (not shown). However, in some embodiments, therapeutic and/ordiagnostic agent delivery device 10, or components thereof, reside(s)outside of the body of the patient.

Therapy delivery device 10 includes an infusion apparatus 14, e.g., acatheter that provides a conduit for delivery of a therapeutic and/ordiagnostic agent, e.g., one or more biological therapeutic and/ordiagnostic agents, genetic therapeutic and/or diagnostic agents, and/orpharmaceutical therapeutic and/or diagnostic agents, to a heart 12. Inthe illustrated embodiment, a distal end 16 of infusion apparatus 14 ispositioned within, and/or fluidly coupled to a vessel, or port formed ina vessel, such as a portion of the aorta 24 of heart 12, and device 10dispenses a precisely timed bolus or dose of at least one therapeutic ordiagnostic agent to aorta 24. In such embodiments, a physicianmanipulates infusion apparatus 14 into fluid communication with anartery, such as the jugular or femoral arteries, and guides distal end16 to the aorta. In other embodiments, distal end 16 is implanted intothe coronary sinus 18 of heart 12 via the great vein or branchesthereof. In some embodiments, distal end 16 includes a needle, which canbe retractable, to facilitate pericardial therapeutic and/or diagnosticagent delivery.

Therapeutic and/or diagnostic agent delivery device 10 includes a sensor22 to detect closure of an aortic valve 26 of heart 12, and delivers oneor more therapeutic and/or diagnostic agents via infusion apparatus 14upon detection of the closure. Sensor 22 generates a signal as afunction of the activity of heart 16, e.g., the mechanical contractionsand/or electrical depolarizations of heart 16. In various embodiments,sensor 22 takes the form of a microphone, a flow sensor, anaccelerometer, a pressure sensor, an oximeter, or the like. Device 10processes the signal generated by sensor 22 to detect closure of aorticvalve 26.

In the illustrated embodiment, sensor 22 is carried on a lead 20 andpositioned within coronary sinus 18 along a left ventricular free wallof heart 12. In exemplary embodiments where sensor 22 is positioned asillustrated, sensor takes the form of an accelerometer that sensesmotion of and vibration within the free wall of the left ventricle. Inthis regard, co-pending non-provisional U.S. patent application Ser. No.10/377,207 filed on 28 Feb. 2003, invented by Edward Chinchoy andentitled, “METHOD AND APPARATUS FOR OPTIMIZING CARDIAC RESYNCHRONIZATIONTHERAPY BASED ON LEFT VENTRICULAR ACCELERATION” is hereby incorporatedby reference herein. In some embodiments, sensor 22 takes the form of anaccelerometer positioned within a right ventricle, atria or ismechanically coupled to a portion of septal wall tissue of a heart. Inthis regard, co-pending non-provisional U.S. patent application Ser. No.10/631551 filed on 30 Jul. 2003, invented by Robert Nehls and ToddSheldon and entitled, “METHOD OF OPTIMIZING CARDIAC RESYNCHRONIZATIONTHERAPY USING SENSOR SIGNALS OF SEPTAL WALL MOTION” is hereby alsoincorporated by reference herein. Suitable accelerometers for thepractice of the invention include piezoceramic accelerometers, amongmany others known and/or used in the cardiac pacing arts.

The invention is not however limited to embodiments where sensor 22takes the form of an accelerometer. For example, in some embodiments,sensor 22 comprises a pressure sensor implanted in the aortic arch tomeasure the aortic pressure, the left ventricle to measure leftventricular pressure, pulse pressure, the right ventricle to measureright ventricular pressure, or the systemic arteries to measure arterialpressure. In other embodiments, sensor 22 takes the form of a similarlypositioned flow sensor or oximeter. In some embodiments, a pressure,flow, or oximetery sensor 22 is implanted in the left ventricle byaccessing the right ventricle and puncturing the intraventricular septumof heart 12.

In some embodiments, sensor 22 takes the form of a vibration sensor,e.g. a microphone, that generates a signal that includes vibrationassociated with the closure of aortic valve 26. Such a sensor 22 can beimplanted anywhere within a body of a patient, or positioned on thesurface of the patient. In exemplary embodiments, such a sensor 22 isnot carried on a lead, but is included within a housing of device 10.

The invention is not limited to the above-identified sensors. Further,the invention is not limited to embodiments where device 10 includes asingle sensor 22. Rather, in some embodiments, IMD 10 uses two or moresensors 22 or types of sensors 22 to detect closure of aortic valve 26.

FIG. 2 is a block diagram further illustrating device 10 of FIG. 1. Asillustrated in FIG. 2, therapeutic and/or diagnostic agent deliverydevice 10 includes processor 40 that communicates with pump 42 andmonitor module 44. Processor 40 takes the form of one or more of amicroprocessor, digital signal processor, application specificintegrated circuit, field-programmable gate array, and other logiccircuitry programmed to provide the functionality ascribed to processor40 herein. In some embodiments, device 10 includes a memory that storesprogram instructions. The program instructions control processor 40 toprovide the functions ascribed to it herein.

Pump 42 typically includes fill port 46 to facilitate filling andre-filling of reservoir 48. Reservoir 48 holds a therapeutic and/ordiagnostic agent or a mixture of therapeutic and/or diagnostic agents.In some embodiments, a therapeutic and/or diagnostic agent deliverydevice 10 includes one or more pumps 42 to deliver a therapy agent or amixture of therapy agents stored in one or more reservoirs 48 to a heartvia one or more infusion apparatuses 14. However, for ease ofillustration, therapy agent delivery device 10, as shown in FIG. 2,includes one of each.

Processor 40 controls pump 42 to create a pressure gradient, therebyforcing the therapeutic and/or diagnostic agent stored in reservoir 48along infusion apparatus 14. In some embodiments, a distal end ofinfusion apparatus 14 is implanted near heart 12 (FIG. 1). In exemplaryembodiments, infusion apparatus 14 is implanted in the aortic arch, asshown in FIG. 1. Another exemplary implant location, as described above,includes any location fluidly coupled to coronary sinus 18.

As discussed above, in exemplary embodiments the signal generated bysensor 22 includes one of a left or right ventricular accelerometersignal, a left or right ventricular flow signal, an aortic pressuresignal, a left or right ventricular pressure signal, a systemic arterialpressure signal, an electrogram signal and a phonocardiogram signal.Upon receiving such a signal, monitor module 44 analyzes the signal todetect closure of the aortic valve. In some embodiments, monitor module44 applies analog analysis, such as envelope detection, and monitormodule 44 includes analog filters, sense threshold circuits and the liketo identify the closure of aortic valve 26. In some embodiments monitormodule 44 applies digital signal analysis techniques, such as waveletanalysis and/or Fourier transforms, to the signal to identify theclosure of aortic valve 26.

In digital signal analysis embodiments of device 10, monitor module 44converts the signal from an analog signal into a digital signal. In someembodiments, monitor module 44 does not process the digital signal, butinstead provides the digital signal to processor 40 for digital signalanalysis and detection of closure of aortic valve 26.

FIG. 3 is a timing diagram illustrating exemplary signals 62 and 64processed by device 10 of FIG. 1 to detect closure of aortic valve 26 ofheart 16. FIG. 3 depicts signals 62 and 64 over a single cardiac cycle.Region 66 indicates a period of time during which aortic valve 26 closeswhen onset of diastolic coronary perfusion occurs. A therapeutic and/ordiagnostic agent delivery device 10 detects the aortic valve closure byidentifying one or more morphological characteristics of signals 62, 64.

Monitor module 44 receives signals 62 and 64 from sensors 22. In theillustrated example, signal 62 is an aortic pressure signal generated bya pressure sensor 22 as a function of the aortic pressure. Further,signal 64 is an accelerometer signal generated by an accelerometersensor 22 as a function of the motion of the left ventricular wall. Insome embodiments, the monitor module converts signals 62, 64 from analogsignals to digital signals and delivers the digital signals to processor40 for monitoring. In other embodiments, monitor module processes thesignal to detect aortic valve closure using analog or digital signalprocessing techniques as discussed above.

As illustrated in FIG. 3, aortic pressure signal 62 comprises fairlyconstant amplitude for the first half of the cardiac cycle. During thistime the heart is in diastole and the aortic valve is closed. Once theheart enters systole the aortic valve opens and blood from the leftventricle is pumped into the aorta increasing the amplitude of aorticpressure signal 62. When the aortic valve closes again and a localminimum occurs within region 66. This local minimum is known as thedicrotic notch and further indicates diastolic coronary perfusion.Processor 40 or monitor module 44 detects this local minimum to detectclosure of the aortic value using digital, e.g., Fourier or wavelet,analysis.

Left ventricular accelerometer signal 64 measures the motion of theouter wall of the left ventricle. In some embodiments, a leftventricular accelerometer sensor 22 is implanted via the coronary sinus,as illustrated in FIG. 1, near the left ventricular free wall tofacilitate measuring this motion. As the cardiac cycle begins smalldisturbances are noted that correspond to ventricular filling. Asventricles contract the absolute amplitude of signal 64 increases. Atregion 66, where closure of aortic valve 26 occurs, the absoluteamplitude of signal 64 again increases. Processor 40 or monitor module44 detects this second amplitude increase using, for example, Fourier orwavelet analysis, or analog envelope detection circuitry, and the like.

In some embodiments where monitor module 44 or processor 40 appliesdigital signal analysis to identify morphological characteristics ofsignals 62 and/or 64 associated with aortic valve closure, module 44 orprocessor 40 compares the signal to a template that includes, forexample, local minimums, maximum slopes, minimum slopes, local maximums,or some other fiducial point. Device 10 can further tailor templatesusing learning algorithms to fit specific patient data, therebyimproving accuracy.

In some embodiments, the pump 42 delivers the therapeutic and/ordiagnostic agent for a set period of time. The set period of timepertains to heartbeats and various embodiments deliver the therapeuticand/or diagnostic agent in various modes. Exemplary modes includecontinuous delivery, i.e., delivery every heartbeat and delivery everynth beat. For example, n can equal 5 and thus delivery occurs every5^(th) heart beat. Other exemplary modes enable delivery of the drugbased on physiological parameters. For example, a patient with a weakheart requires epinephrine to strengthen cardiac performance. Thus, pump42 delivers epinephrine based on measures of the strength of the heart.Further embodiments can incorporate modes of delivery where thetherapeutic and/or diagnostic agent is delivered according to a schedulestored in a memory.

FIG. 4 is a flowchart illustrating an exemplary method employed bymedical device 10 of FIG. 1 to deliver a therapeutic and/or diagnosticagent to the heart. Monitor module 44 receives a left ventricularaccelerometer signal from sensor 22 (80), which resembles signal 64 ofFIG. 3. Monitor module 44 analyzes the signal to detect closure ofaortic valve 26 (82).

In exemplary embodiments described above, monitor module 44 appliesanalog analysis to detect the closure of aortic valve 26. For example,monitor module 44 can apply envelope detection to the signal to detectclosure of aortic valve 26. If monitor module 44 does not detect closureof the aortic valve then monitor module 44 continues to receive andanalyze the signal (44).

In the event that monitor module 44 detects the closure of aortic valve26, module 44 provides an indication to processor 40, which controlspump 42 to initiate delivery of a therapeutic and/or diagnostic agentfrom reservoir 48 to the heart (86). Delivery of the therapeutic and/ordiagnostic agent during diastolic coronary perfusion post aortic valveclosure can allow for a controlled relative amount of therapeutic and/ordiagnostic agent to perfuse the heart.

Device 10 delivers one or more therapeutic and/or diagnostic agents ormixtures of therapeutic and/or diagnostic agents in accordance with theinventions. In particular, device 10 delivers any one or combination ofgenetic agents, biological agents and pharmaceutical agents to providespecific therapies to a patient. For example, in some embodiments,device 10 delivers pharmaceutical agents, such as epinephrine anddigitalis, to enhance cardiac performance. Other pharmaceutical agentssuch as t-PC can be delivered to dissolve blood clots in heart 12.Device 10 can further deliver genetic agents to provide therapy forischemia. For example, device 10 can deliver stem cells to replace dyingheart cells.

FIG. 5 is a conceptual diagram illustrating another exemplary medicaldevice 90 that delivers a therapeutic and/or diagnostic agent to a heartaccording to the invention. Therapeutic and/or diagnostic agent deliverydevice 90, as shown in FIG. 5, delivers a therapeutic and/or diagnosticagent to heart 92 via infusion apparatus 94, e.g. a catheter.Furthermore, therapeutic and/or diagnostic agent delivery device 90receives a signal from sensor 96 via filaments included within lead 98.Based on this signal, therapeutic and/or diagnostic agent deliverydevice 90 delivers the therapeutic and/or diagnostic agent.

In particular, FIG. 5 illustrates alternative locations for a sensor 96and distal end 100 of infusion apparatus 94 that are employed accordingto some embodiments of the invention. Infusion apparatus 94, as shown inFIG. 5, is implanted into the coronary sinus of heart 92. Sensor 96 isinserted into the right ventricle of heart 92. These exemplary implantlocations can be selected due to the ease of positioning lead 98 andinfusion apparatus 94 in these positions relative to the positions oflead 20 and infusion apparatus 14 illustrated in FIG. 1.

Infusion apparatus 94 delivers a therapeutic and/or diagnostic agent tothe coronary arteries, similar to infusion apparatus 14. However,apparatus 94 access the coronary arteries via the right atrium of heart92. Nonetheless, therapeutic and/or diagnostic agents delivered bydevice 90 via infusion apparatus 94 perfuse heart 92.

Sensor 96 generates a signal as a function of the acoustics ormechanical motion within the right ventricle of heart 92. Other acousticlocations where sensor 96 can monitor heart 92 include the housing ofdevice 90, the skin surface of patient proximate to heart 92, and thelike. Placement of sensor 96, e.g., a microphone, pressure transducer,or accelerometer in either the right or left ventricle provides sensor96 proximity to heart 92 to facilitate sensing of the noise and/ormotion associated with the closure of the aortic valve. Thus thisposition is viable to monitor heart activity and more particularly theclosure of the aortic valve (not shown) of the heart 92.

FIG. 6 is a diagram illustrating another exemplary medical device 110that delivers a therapeutic and/or diagnostic agent to a heart 112according to the invention. Therapeutic and/or diagnostic agent deliverydevice 110, as shown in FIG. 6, delivers a therapeutic and/or diagnosticagent to heart 112 via infusion apparatus 114, which is shown as acatheter. Furthermore, therapeutic and/or diagnostic agent deliverydevice 110 receives a signal from sensor 116 via filaments includedwithin lead 118. Similar to therapy agent delivery device 90, therapyagent delivery device 110 delivers the therapeutic and/or diagnosticagent based on the signal.

In particular, FIG. 6 illustrates a further alternative location fordistal end 120 of infusion apparatus 114 that is employed according tosome embodiments of the invention. Infusion apparatus 114, as shown inFIG. 6, is implanted into left ventricle 122 by puncturing a portion ofventricular septal wall tissue or a portion of the apex 124 of heart112. Other exemplary implant procedures exist to implant distal end 120into left ventricle 122. For example, distal end 120 can be implantedinto right ventricle 126 via the right atrium of heart 112. Once in theright ventricle, distal end 120 of infusion apparatus 114 is insertedinto left ventricle 122 via a puncture in the septum between rightventricle 126 and left ventricle 122. A further example of implantingdistal end 120 into left ventricle 122 includes inserting distal end 120into the right atrium of heart 112. Distal end 120 is then inserted intothe left atrium of heart 112 via a puncture in the septum between theright and left atrium. From the left atrium, distal end 120 of infusionapparatus 114 is implanted in left ventricle 122.

In some embodiments, distal end 120 of infusion apparatus 114, afterbeing inserted into left ventricle 122, is fed through the aortic valveinto the aorta of heart 112. In these embodiments, wherein distal end120 is implanted into the aorta via left ventricle 122, infusionapparatus 114 delivers a therapeutic and/or diagnostic agent similar toinfusion apparatus 14. However, the implant locations differ in thatinfusion apparatus 14 is implanted via the femoral or jugular arteries,as described above. Nevertheless, therapeutic and/or diagnostic agentsdelivered by device 110 via infusion apparatus 114 perfuse heart 112. Inembodiments where a therapeutic and/or diagnostic agent is delivered toleft ventricle 122, a smaller percentage of the delivered therapeuticand/or diagnostic agent may perfuse heart 112 than is possible withdirect aortic delivery.

Sensor 116 generates a signal similar to that of sensor 96. The signalrepresents acoustics or mechanical motion, or both acoustics andmechanical motion of heart 112. Similar to sensor 96, locations ofsensor 116 include the housing of device 110, on the skin of the patientproximal to heart 112, within heart 112, as shown by FIG. 6, and thelike. Placement of sensor 116, which includes similar sensor types assensor 96 listed above, in either the right or left ventricle providessensor 116 proximity to heart 112 to facilitate detection of the closureof the aortic valve.

The invention as described above provides for the efficient delivery ofa therapeutic and/or diagnostic agent to a heart. In particular, atherapeutic and/or diagnostic agent delivery device in accordance withthe invention may delivery a therapeutic and/or diagnostic agent suchthat a majority of the therapeutic and/or diagnostic agent perfuses theheart. Moreover, the therapeutic and/or diagnostic agent delivery devicemay ensure this by detecting the closure of the aortic valve anddelivering the therapeutic and/or diagnostic agent during diastoliccoronary perfusion. A number of embodiments are described above thatillustrate therapeutic and/or diagnostic agent delivery devices inaccordance with these techniques.

Various embodiments of the invention have been described. However, oneskilled in the art will appreciate that various medications can be madeto these embodiments without departing from the scope of the invention.For example, although described herein in the context of a singledevice, a device according to the invention can include components,e.g., a pump, a processor, and/or a sensor; one or more of which may bedisposed external to the body. In some embodiments, a catheter and/orlead percutaneously access a position within a patient. For example, insome embodiments and external device according to the invention could beused to perfuse the heart with a therapeutic and/or diagnostic agentduring a stay in a hospital. Finally, all forms of therapeutic and/ordiagnostic agents are intended to benefit from the teaching of thepresent invention, including without limitation such agents whenrendered at an appropriate viscosity or when diluted in a fluid medium,and the like. These and other embodiments are within the scope of thefollowing claims.

1. A non-transitory computer-readable medium comprising instructionsthat cause a programmable processor to: receive a signal that reflectsactivity of a heart; process the signal to detect closures of an aorticvalve of the heart; and control a pump to deliver a therapeutic and/ordiagnostic agent to the heart responsive to a plurality of thedetections of aortic valve closures by delivering controlled amounts ofthe therapeutic and/or diagnostic agent over the series of heartbeats,during time periods in which aortic pressure increases responsive toclosures of the aortic valve.
 2. The computer-readable medium of claim1, wherein the instructions that cause a programmable processor toprocess the signal further comprise instructions that cause aprogrammable processor to process at least one of a ventricularaccelerometer signal, a ventricular flow signal, a ventricular pressuresignal, an aortic pressure signal, a systemic arterial pressure signal,an electrogram signal, a phonocardiogram signal.
 3. Thecomputer-readable medium of claim 1, wherein the instructions that causea programmable processor to process the signal further compriseinstructions that cause a programmable processor to digitally processthe signal.
 4. The computer-readable medium of claim 3, wherein theinstructions that cause a programmable processor to digitally processthe signal further comprise instructions that cause a programmableprocessor to digitally process a pressure signal to detect a dichroticnotch within the signal.